Abstract While the thermogenic properties of brown adipose tissue (BAT) are well known, we recently reported previously unknown cardioprotective properties of BAT against catecholamine-induced myocardial injury. In preliminary studies that support the present proposal, we identified bone morphogenetic protein 3b (BMP- 3b) as a cardioprotective adipokine that may mediate BAT-related cardioprotection. The objective of this proposal is to further investigate the cardioprotective effects of BAT and BMP-3b in a murine model of myocardial ischemia-reperfusion (I/R) injury. In preliminary studies, we demonstrated that mice that are deficient in the uncoupling protein 1 (UCP1), a protein synthetized by BAT and required for BAT thermogenic function, develop greater myocardial infarction (MI) size than WT mice after I/R injury. We identified BMP-3b, a protein of previously unknown cardiovascular properties, as an adipokine synthesized and secreted by the activated BAT of WT but not of UCP1-deficient mice. We demonstrated that BMP-3b treatment decreased MI size after I/R injury in WT mice. In preliminary studies, BMP-3b increased the levels of P-Smad1/5/8 and S1177P-NOS3, and decreased apoptosis in serum-deprived cardiomyocytes (CMs). Furthermore, BMP-3b increased left ventricular (LV) P-Smad1/5/8 and STAT3 levels after I/R. To further investigate the cardioprotective role of BAT in I/R injury, we will determine whether restoring functional BAT in UCP1-/- mice and increasing functional BAT in WT mice limit MI size. In these studies, we will transplant BAT from WT mice into UCP1-/- and WT mice prior to myocardial injury. By studying BMP-3b-/- and BAT-specific BMP-3b-/- mice, we will elucidate whether BMP-3b is the adipokine in BAT, and BAT the BMP-3b producing tissue that is required to limit I/R injury. To investigate the mechanisms underlying the cardioprotective effects of BMP-3b, the role of the BMP, NOS3 and STAT3 pathways in the cardioprotective effect of BMP-3b will be assessed using both isolated mouse adult CMs and the in vivo I/R murine model. The CM receptors engaged by BMP-3b will be identified. As a first step toward applying the results to humans, we will investigate whether BMP-3b is secreted by human brown adipocytes, and whether myocardial infarction increases BMP-3b in the plasma of human patients. To further investigate the potential clinical applicability of BMP-3b treatment in I/R injury, we will test the effect of varying BMP-3b dose, and time of delivery relative to onset of injury, on the extent of myocardial damage in the in vivo murine I/R model. Successful completion of these aims will define and elucidate a novel cardioprotective effect of BAT in myocardial I/R injury and will characterize a previously unknown cardioprotective adipokine secreted by BAT, BMP-3b. The proposal is a first step toward identifying new cardioprotective therapies that may decrease myocardial I/R injury.